In recent years, there has been considerable effort to provide systems that are capable of controlled release of drugs in animals, including humans. Some drugs can only be administered to a patient by injection. Controlled release of such drugs has the advantage that the patient does not need to be subjected to multiple injections, but instead only one or a few injections with the controlled release system would suffice.
Some injections into areas of the patient's body are (very) painful. Examples of such difficult to dose areas are the eyes, the (synovial) joints, the muscles or the spine. Injection with a drug in a controlled release system will limit the amount of injections needed and will enhance the chance that a patient will continue with the therapy. This will greatly increase the success of the treatment.
Controlled release systems that are very suitable for being injected into such difficult to dose areas are thermogels based on compositions comprising polymers. The polymers have the unique property that at low temperatures they are water soluble, whereas at higher temperatures the polymers form a gel. Preferably, for use as a system that is capable of controlled release, the polymer is soluble in the solvent used at room temperature (e.g. 21° C.) and forms a gel once injected into the body (temperature in the range from 30 to 42° C.).
A gel (or a hydrogel in the context of the present invention) is a network of polymer chains that are hydrophilic and contain a substantial amount of water (for example between 50 and 99% water, preferably between 66 and 85% water). The gel shows no flow in a vial tilt test: when a glass vial which contains the gel is turned upside down, no flow of the gel is observed during 15 seconds observation time.
Since different drugs require a different drug administration regime, there is a desire to make thermogels having a tunable release profile.
Methods to tune release profiles of thermogels of BAB-type tri-block copolymers have been described by Yu et al., in ‘Mixing a sol and a precipitate of block copolymers with different block ratios leads to an injectable hydrogel’ in Biomacromolecules, 2009, 10, 1547-1553 and in CN200910049664. Yu et al. describe a method to obtain a thermoreversible physical hydrogel by mixing an aqueous solution of an BAB-type triblock copolymer poly(D,L-lactic acid-c-glycolic acid)-b-polyethylene glycol-b-poly(D,L-lactic acid-co-glycolic acid), as indicated PLGA-PEG-PLGA, with a precipitate of a similar copolymer but with a different block ratio. According to Yu et al., this method provides a very convenient approach to design injectable thermogelling biomaterials with a broad adjustable window, which copolymer mixture platform can potentially be used in drug delivery.
Also, WO 01/82970 A1 discloses a water-soluble, biodegradable reverse thermal gelation system comprising a mixture of at least two types of tri-block copolymers. The drug release and gel matrix erosion rates of the mixture of copolymers may be modulated by various parameters such as the hydrophobic/hydrophilic component contents, polymer block concentrations, molecular weights and gelation temperatures, and weight ratios of the tri-block copolymer components in the mixture.
However, from a regulatory point of view, every time a different polymer is used in a thermogel blend, the new mixture needs to go through a new regulatory approval process before the national or regional drug approval authority (such as the Federal Drug Administration (FDA) in the US or its European equivalent the European Medicines Agency (EMEA) in Europe). This will prolong the very important time-to-market considerably.